This invention relates to newly synthesized platinum complexes with hydrophobic properties. The use of liposomes incorporating these new and previously synthesized complexes in anti-tumor chemotherapy is also described.
Cis-platinum (CDDP) is a highly effective drug in the treatment of several neoplastic diseases in humans (Loehrer et al (1984) Ann. Int. Med. V 100, pp 704-713). However, its use is limited by severe systemic toxicity, particularly nephrotoxicity and neurotoxicity (Zwelling et al Platinum Complexes. In: Pharmacologic principles of cancer treatment (1982) Ed by B. A. Chabner, Saunders, Philadelphia, Pa.). In an attempt to modify the therapeutic index of CDDP, new derivatives have been synthesized during the last decade. However, the development of some promising analogues has been prevented by their low hydrosolubility, which decreases their potential for clinical use (Burchenal et al (1979) Cancer Treat. Rep. V 63, pp 1493-1497).
Liposomes are lipid vesicles which may form spontaneously upon addition of an aqueous solution to a dry lipid film (Mayhew et al, In: Liposomes (1983) Ed by Marc J. Ostro, Marcel Dekker, Inc., New York, N.Y.). Liposomes may be used as drug carriers of hydrophobic or hydrophilic drugs entrapped in their hydrophobic or hydrophilic compartments respectively. Multilamellar liposomes are multilayer lipid vesicles (MLV) that are particularly suited for carrying hydrophobic drugs since their hydrophobic compartment is larger than their hydrophilic compartment. When injected intravenously (iv) in animals, (Kasi et al (1984) Int. J. Nucl. Med. Biol. V 11 pp 35-37, Lopez-Berestein et al. (1)(1984) Cancer Drug Deliv. V 1, pp 199-205) and humans (Lopez-Berestein et al (2)(1984), Cancer Res. V 44, pp 375-378), MLV concentrate in the liver, spleen and other organs rich in reticuloendothelial (RES) cells.
Liposomes have been previously used in vitro to deliver chemotherapeutic agents, (Mayhew et al, Liposomes (1983), Ed by Ostro, Marcel Dekker, Inc., New York, N.Y.) and immunomodulators and anti-fungal agents in vitro (Mehta et al (1984), Immunology V 51 pp 517-527, and in vivo in animals (Lopez-Berestein et al (4)(1984) Clin Exp Metastasis V 2 pp 127-137 and Lopez-Berestein et al (1983), J Inf Dis V 147, pp 937-945) and in humans (Lopez-Berestein et al (1985) J. Inf. Dis. V 151 pp 704-710).
Recent studies show that liposomes can reduce certain types of drug-related toxicities such as doxorubicin cardiotoxicity (Forssen et al (1981) Proc. Natl. Acad. Sci. V 78 pp 1873-1877, Olson et al (1982), Eur. J. Cancer Clin. Oncol. V 18 pp 167-176, Gabizon et al (1982) Cancer Res. V 42 pp 4734-4739, Herman et al (1983) Cancer-Res. V 43 pp 5427-5432) and CDDP nephrotoxicity, (Freise et al (1982), Arch. Int. Pharmacodynamie Therapie V 258 pp 180-192) and may increase antitumor activity as a result of a slow release mechanism (Mayhew et al (1978) Ann. N.Y. Acad. Sci. V 308, pp 371-386, Patel et al (1984) Int. J. Cancer V 34 pp 717-723) a higher drug uptake by tumor cells or due to a more selective organ distribution (Gabizon et al (1983) Cancer Res. V 43, pp 4730-4735 and Mayhew et al (1983), Cancer Drug Deliv. V 1 pp 43-58). In U.S. Pat. No. 4,330,534 N.sup.4 -acylcytosine arabinoside incorporated into liposomes, for example, was found to be therapeutically effective when administered to tumor-bearing animals. In spite of these promising results, the clinical application of antitumor agents encapsulated in liposomes has been delayed, mainly due to formulation, drug stability and large scale production problems.
CDDP has been previously encapsulated in MLV but with a very low encapsulation efficiency (7.4%) and poor stability (75% at 48 hours in 0.9% NaCl solution) (Freise et al (1982) Arch. Int. Pharmacodynamie Therapie V 258 pp 180-192).
In U.S. Pat. No. 4,256,652 are described certain platinum compounds comprising resolved stereoisomers of 1,2 diaminocyclohexane (DACH). The isomers utilized were cis-DACH, trans-RR-DACH and trans-SS-DACH. The platinum compounds described therein contained, in addition to a resolved DACH isomer, two hydrophilic platinum ligands such as bromide, iodide, nitrate, bromoacetate, sulfate or glucuronate. The platinum compounds comprising the trans-RR-DACH were described as often more therapeutically effective than those bearing cis-DACH.
In European Patent Application No. 83306726.7 certain platinum compounds are described which may comprise diaminocyclohexane (non-stereochemically resolved) and do comprise phosphatidyl groups having fatty acid substituents. These compounds are described as largely insoluble in plasma and preferably employed with lipid vesicle carriers. The platinum compound-phospholipid vesicles were preferably prepared by a sonic oscillation procedure which characteristically yields unilamellar vesicles.